Although it is a target of group-specific neutralizing antibodies, gp120 is a weak immunogen, inducing at 50-fold lower antibody titers than observed after infection. We have found a way to introduce into gp120 new protein sequences that are potent immunogens, creating novel gp120 hybrids. If we prime the mice with the potent immunogen and boost with the hybrid, the mice make an accelerated secondary response to the hybrid which is enhanced 20-fold greater than in the non-primed controls. In addition, the priming strategy is capable of overcoming genetic low responsiveness in mice, a situation due to lack of T cell help. Thus, hybrid antigens, by recruiting additional T cell help, make potent immunogens that enhance the intrinsic vaccine potency of gp120. Despite the urgent need for an HIV vaccine in the U.S. and the world, no vaccine has shown potency or efficacy. Our program has proceeded in a stepwise fashion to: a. identify neutralizing sites on gp120 and map them to the CD4 binding site; b. identify insert acceptor sites on gp120, where potent immunogens can be inserted while retaining the neutralizing site; and c. demonstrate carrier effects of the inserted protein on the immunogenicity of the gp120 hybrid antigen. We are now working to produce even more immunogenic hybrids, potentially up to 1,000-fold more potent, due to self assembly of multimers, and we plan to immunize and challenge rhesus monkeys with a titered challenge strain of SHIV. Ref: Berkower, I., Bridgewater, J., Genetic Control of the Immun Response to gp120, AIDS Res 14:893-900, 1998.